title: New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3'-iodo-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors.
abstract: A simple and efficient synthesis of nAChR antagonist (+/-)-7-methyl-2-exo-(3'-iodo-5'-pyridinyl)-7-azabicyclo[2.2.1]-heptane ((+/-)-NMI-EPB) has been developed. Both enantiomers of (+/-)-NMI-EPB were separated by semi-preparative chiral HPLC. The enantiomers manifested a substantial difference in their inhibition binding affinities ((+)-NMI-EPB, K(i)=2310, 1680 pM; (-)-NMI-EPB, K(i)=55, 68 pM). The enantiomers were stereoselectively radiolabeled with (11)C. In the distribution studies in the rodent brain [(11)C](-)-NMI-EPB specifically labeled nAChR whereas [(11)C](+)-NMI-EPB exhibited little specific binding. In the baboon PET study [(11)C](-)-NMI-EPB did not reach steady-state within 90 min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-0816, USA. yongjgao@yahoo.com
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gao
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kuwabara
authors.forename: Hayden T
authors.initials: HT
authors.lastname: Ravert
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Holt
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Mohab
authors.initials: M
authors.lastname: Alexander
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dannals
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006536:Heptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D010215:Papio; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: C509758:7-methyl-2-exo-(3'-iodo-5'-pyridinyl)-7-azabicyclo(2.2.1)heptane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006536:Heptanes; D008024:Ligands; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic